Vascular disease is the leading cause of death in the United States. Neural-tube defects are a major contributor to perinatal morbidity and mortality. Elevated levels of plasma homocysteine (a non-protein amino acid) have been found to correlate with an increased risk of NTDs and vascular disease. Methionine synthase (MS) catalyzes the vitamin B12 dependent, interconversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. This is one of the few homocysteine consuming reactions in the body and reduced MS activity is predicted to lead to increased plasma homocysteine. We have cloned the human MS gene and demonstrated that hyperhomocysteinemia in a subset of patients is in fact due to mutations in the MS gene. Most of the genomic structure of the MS gene has been determined. Once all MS exons have been identified, mutation screening assays will be developed. Families with children affected with NTDs have been screened to determine if MS plays a role in NTD. Initial data has does not show a connection between MS and NTD. We are now testing to see if the enzyme that acts with MS, MS- reductase plays a role in NTD. In addition to the human genetic studies, we have used homologous recombination techniques to create a mouse model of MS deficiency. The phenotype of this mouse is currently being investigated.